Mechanisms of Enhanced Neuroregeneration Associated with the Common Human Single Nucleotide Polymorphism Val66Met
Abstract
Parkinson s disease (PD) is the second most common neurodegenerative disorder, with an estimated 1,000,000 Americans living with this disease. While there are a variety of therapeutic options for treating PD, current therapies do not work uniformly well in all patients, and over time the effectiveness of medications wane and many experience significant side-effects. In this era of precision medicine, we are becoming aware that PD is a complex and heterogeneous disease in which mechanisms causing the disease, the signs and symptoms, and the way an individual responds to treatment can vary from person to person. The goal of precision medicine is to develop the right treatment for the right person at the right time to provide not only an effective therapy but one that is free from deleterious side-effects. Toward the goal of finding new treatment options, scientists have been examining approaches to replace the specific brain cells (i.e., dopamine (DA) neurons) that die in PD. Indeed, grafting new DA neurons into the brain of a person with PD can have remarkable benefit. However, like drug therapies, the success of cell-based therapies varies from person to person. While some show remarkable benefit, others show little-to-no benefit, and still others develop often debilitating side-effects called graft-induced dyskinesias (GID). Scientists have begun to understand how global factors, like the age of a person or the severity of their disease, impacts therapeutic responses to brain cell grafting. Yet, until recently, how a person s genetics might impact DA cell replacement therapy had not been examined. To begin to explore this, we are studying a genetic risk factor called rs6265 that occurs in approximately 20% of all humans. In individuals with the rs6265 gene variation, their neurons fail to release adequate amounts of a growth factor called brain-derived neurotrophic factor (BDNF). BDNF is critical for normal development and function of many neurons, including grafted DA neurons. We previously hypothesized that grafting of new DA neurons in PD patients with the rs6265 gene variant results in impaired development and function of these neurons, and the consequential suboptimal therapeutic benefit and development of GID. To test this idea, we developed a rat model of the human rs6265 gene variant. The rs6265 rats were made parkinsonian and grafted with DA neurons from normal/control rats, called wild-type (WT) rats. Surprisingly, we found that when these WT DA neurons were grafted into the rs6265 host rats, they showed superior neuron development and functional benefit compared to when WT DA neurons were grafted into WT host rats. Unfortunately, rs6265 rats also developed the deleterious GID side-effect. This study was the first to show that: (1) an individual s genetic makeup can impact this experimental therapy that is currently being explored in at least five clinical trials worldwide, and (2) WT neurons can be induced to develop an enhanced regenerative benefit when transplanted into a rs6265 host brain. While enhanced functional benefit in an environment of diminished BDNF availability seems paradoxical, the rs6265 gene variant has been indicated in enhanced functional recovery following stroke in rs6265 mice and traumatic brain injury (TBI) in human combat Veterans. We propose here to undertake a set of studies to test two hypotheses that will allow us to begin to understand how to harness the beneficial, while avoiding the detrimental, effects of the common human rs6265 gene variant in the context of individualized cell-based therapy for PD. First, we hypothesize that the diminished BDNF availability in rs6265 brains prevents normal maturation of grafted DA neurons leading to abnormal connections between graft and host brain resulting GID side-effects. We will test this hypothesis by providing exogenous BDNF to rs6265 graft recipient brains. We predict that this will allow for normal matu
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210804
Entities
People
- Margaret Caulfield
Organizations
- Michigan State University
- United States Army